Machine Learning-driven Protein Library Design: A Path Toward Smarter Libraries

Proteins are small yet valuable biomolecules that play a versatile role in therapeutics and diagnostics. The intricate sequence-structure-function paradigm in the realm of proteins opens the possibility for directly mapping amino acid sequence to function. However, the rugged nature of the protein fitness landscape and an astronomical number of possible mutations even for small proteins make navigating this system a daunting task. Moreover, the scarcity of functional proteins and the ease with which deleterious mutations are introduced, due to complex epistatic relationships, compound the existing challenges. This highlights the need for auxiliary tools in current techniques such as rational design and directed evolution. To that end, the state-of-the-art machine learning can offer time and cost efficiency in finding high fitness proteins, circumventing unnecessary wet-lab experiments. In the context of improving library design, machine learning provides valuable insights via its unique features such as high adaptation to complex systems, multi-tasking, and parallelism, and the ability to capture hidden trends in input data. Finally, both the advancements in computational resources and the rapidly increasing number of sequences in protein databases will allow more promising and detailed insights delivered from machine learning to protein library design. In this chapter, fundamental concepts and a method for machine learning-driven library design leveraging deep sequencing datasets will be discussed. We elaborate on (1) basic knowledge about machine learning algorithms, (2) the benefit of machine learning in library design, and (3) methodology for implementing machine learning in library design.